The overall purpose of this proposal is to improve understanding of the pulmonary microcirculation and lung fluid balance before and after birth. The project includes studies to examine developmental differences in pulmonary microvascular pressures and protein permeability, pathways and mechanisms invovled in prenatal and postnatal lung luminal liquid clearance, and the pathogenesis and prevention of lung microvascular injury associated with premature birth. Pulmonary hemodynamics, lung fluid filtration and microvascular protein permeability will be assessed in fetal and newborn lambs by various experimental methods, including measurement of lung lymph flow and lymph protein clearance, direct micropuncture measurement of alveolar liquid and pulmonary microvascular pressures, indicator dilution studies to quantify changes in lung luminal liquid volume over time, gravimetric determination of lung water content, and in vitro studies of lung epithelial cell ion transport. Specific aims are: (1) to compare lung microvascular protein permeability of unanesthetized premature and term fetal lambs by assessing their pulmonary vascular and lymph flow responses to rapid intravenous saline infusion and left atrial pressure elevation; (2) to measure by direct micropuncture liquid pressures in potential air spaces and small pulmonary arterioles and venules at the surface of the lung, with and without air inflation, in living fetal lambs; (3) to determine the importance of the pleural space as a pathway for alveolar liquid clearance in fetal and newborn lambs; (4) to see if hypoproteinemia slows lung liquid removal in newborn lambs; (5) to compare cation transport in lung epithelial cells harvested from preterm lambs, with and without preceding respiratory distress; (6) to see if granulocytes contribute to the abnormal lung vascular protein permeability associated with respiratory distress in preterm lambs; and (7) to test the efficacy of surfactant replacement in preventing or attenuating the lung endothelial injury that occurs in lambs after premature birth. Pulmonary edema is an important component of many types of newborn lung disease. The proposed work should help to clarify how these conditions develop and by what means they can be managed most effectively.